Cognitive impairment, and its associated psychosocial and vocational functional impairments, occurs in many patients with bipolar disorder even when mood symptoms are adequately treated. Despite its importance, no validated treatments exist for cognitive impairments in bipolar disorder. We propose to enroll 120 subjects with bipolar disorder in a 16-week randomized, double blind, placebo controlled study to assess the efficacy of galantamine (an acetyl cholinesterase inhibitor) for the treatment of functional and cognitive impairments in bipolar disorder. Before the onset of medication treatment and at the end of the study we will administer a battery of neuropsychological tests and proton magnetic resonance spectroscopy (1H-MRS) to measure N-acetylaspartate (NAA, a marker of neuronal viability) from the left and right hippocampus. We will use 1H-MRS data to investigate the relation between neuroprotective effects of galantamine (as reflected by NAA levels) and improvement of cognitive deficits in bipolar subjects. All clinical characterization of bipolar subjects, neuropsychological tests and treatment with galantamine or placebo will be conducted in the Bipolar Clinical and Research Program at Massachusetts General Hospital; magnetic resonance spectroscopy assessments will be performed at the Brain Imaging Center at McLean Hospital. We are particularly well prepared to undertake these studies as our research team uniquely combines expertise in clinical pharmacology research, neurocognitive and functional evaluations and magnetic resonance spectroscopy assessments in subjects with bipolar disorder. Demonstrating the efficacy and safety of galantamine for the treatment of cognitive and functional impairment in bipolar disorder will be a major advancement for a significant clinical and public health problem. This translational study will also explore the relationship between cognitive dysfunction and markers of neuronal viability in specific brain areas to allow us to better understand the pathophysiology of cognitive dysfunction in mood disorders. [unreadable] [unreadable] [unreadable]